Abstract Systemic lupus erythematosus is an incurable autoimmune disease characterized by pathogenic autoantibodies that potentiate inflammatory injury in tissues such as skin, lungs and kidneys. Lupus patients also experience neurologic symptoms that range from severe headache and seizures to neuropsychosis and are collectively referred to as CNS Lupus. We propose that neurologic symtoms result from peripheral interferon alpha that enters the brain and activates the microglia and complement -dependent pruning pathway leading to synapse loss in brain regions involved in cognition, spatial memory and social behavior. Studies in murine models of lupus suggest that peripheral immune cells and autoantibody may penetrate the blood brain barrier and induce pathology. However, in lupus patients symptoms of neuropsychosis are often detected early in disease suggesting that other factors might be involved in injury without destruction of the blood brain barrier. In our own study using a murine model of lupus, preliminary results identify an age-dependent significant increase in the frequency of activated microglia that are positive for uptake of neuronal synaptic material. Remarkably, the lupus mice develop changes in behavior that correlate with synapse loss. The pattern of microglia activation and synaptic pruning is similar to that observed during early neural development where selective synapse elimination is normal. Notably, treatment of the lupus mice in vivo with anti-interferon receptor antibody was protective. The objective of this proposal is to test our hypothesis that peripheral cytokines such as type I interferon trigger a microglia-dependent synaptic pruning program leading to increased elimination of synapses that could explain the neurological symptoms observed in lupus. The following two aims are proposed. Specific aim 1: Test the hypothesis that microglia-mediated synaptic pruning becomes activated in SLE. Based on our preliminary data, we predict that microglia-dependent synapse loss occurs in SLE mouse models and that activation of the classical complement cascade is required for this process. Specific aim 2: Test the hypothesis that increased type I interferon signaling in SLE promotes CNS dysfunction We predict that type I interferon-stimulated microglia activate a synapse pruning gene program leading to inappropriate engulfment of neuronal material and development of cognitive and social dysfunction. Moreover, preliminary results suggest that treatment with anti-IFNAR may be protective and prevent synapse loss.